Our results to date indicate that HIV disease results in early brain involvement, produces neurodegeneration, and yields a slowly progressive neurocognitive disorder with "fronto-striatal" features that is associated with increased social morbidity and mortality. The aims in the renewal period are: (1) to confirm that synaptodendritic pathology underlies the in-life neurocognitive and neuroanatomic (quantitative MRI) changes seen in AIDS; (2) to determine selective vulnerability of neuronal subpopulations to discrete mechanisms of injury - specifically, to determine whether excitatory neurones are susceptible to direct damage mediated by gpl20, whereas interneurones are more susceptible to damage mediated by excessive release of cytokines; (3) to examine the role of neurotrophic factors in neuronal injury; (4) to determine whether there is restricted expression of HIV regulatory genes, suggesting an "abortive" infection preceding frank HIV encephalitis. Additional aims are: (1) to relate the evolution of fronto-striatal and limbic-cortical patterns of cognitive deficit to in vivo (MRI morphometry) and postmortem measures of regional structural change; (2) to determine potential reversibility of neurocognitive disorder via limited phase II trials of promising agents such as D4T; (3) to determine the role of CMV as a copathogen underlying later stage cognitive disorder; (4) to determine the predictive utility of CSF/virological, newly developed neurocognitive, psychophysical (visual function), and immunogenetic techniques to identity those at risk for HIV or CMV neurocognitive disorder. The research plan calls for continued annual (q 6 mo if T4<100) follow-up of 372 HIV+ and HIV- men and women from the existing HNRC cohort. An additional 200 persons with AIDS and 50 HIV- controls will be recruited over the first two years of the study. These are required in order to continue diversifying our sample to emerging high-risk groups - i.e., women, persons of color - and to assure an adequate sample of brains at postmortem that are free of significant opportunistic infection. The research plan will be effected through a reorganized HNRC structure consisting of five cores (Coordinating, including Statistics and Data Management Units; Clinical Assessment, including a d4T treatment trial; Neurobehaviora1; Virology; Neuropathology) and five projects (HIV Gene Expression/Neurotrophic Factors; MRI/Information Processing/Neuropathology; CMV/Immunogenetic; CMV/Neurocognitive; and Visual Functioning). The significance of the HNRC stems from its unique multidisciplinary focus on mechanisms underlying neurocognitive and neuropathological complications of HIV. Beyond being able to shed light on critical questions involving neuropathogenesis, the HNRC is being developed as a national resource accessible to investigators requiring data or samples derived from the largest neurobehaviorally-characterized cohort extant that has been followed to neuropathological confirmation.